Blood plasma has been shown to generate fibrinolytic activity independently of cellular plasminogen activators. Activation of Hageman factor leads to coagulation via the intrinsic pathway, generation of bradykinin and evolution of plasmin. While it is generally agreed that activated Hageman factor does not activate plasminogen directly, there is disagreement over the nature of the intervening reactions. This project would further clarify the plasma fibrinolytic pathway by characterizing the plasminogen proactivator, the zymogen whose activated form cleaves plasminogen to plasmin. The proactivator would be purified to chemical homogeneity from bovine plasma. Both proactivator and the activated molecule would be characterized biologically and chemically, including partial sequencing to establish the molecular events involved in the activation reaction. It could be decided whether the proactivator were identical with prekallikrein, a point debated in the literature. Fibrinolysis is essential to maintenance of the hemostatic balance, but it is not known whether in vivo plasmin generation is due primarily to the plasma pathway or to enzymes derived from tissues. Characterization of the plasma fibrinolytic pathway would contribute to resolution of this important question.